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ALVAC®-HIV and AIDSVAX® B/E Prime-Boost HIV-1 Preventive Vaccine Regimen The End of the Beginning

RV 144. ALVAC®-HIV and AIDSVAX® B/E Prime-Boost HIV-1 Preventive Vaccine Regimen The End of the Beginning. Nelson L. Michael, MD, PhD Colonel, Medical Corps, U.S. Army Director, U.S. Military HIV Research Program (MHRP) HVTN Meeting, Seattle, 18 November 2009. RV 144.

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ALVAC®-HIV and AIDSVAX® B/E Prime-Boost HIV-1 Preventive Vaccine Regimen The End of the Beginning

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  1. RV 144 ALVAC®-HIV and AIDSVAX® B/E Prime-BoostHIV-1 Preventive Vaccine Regimen The End of the Beginning Nelson L. Michael, MD, PhD Colonel, Medical Corps, U.S. Army Director, U.S. Military HIV Research Program (MHRP) HVTN Meeting, Seattle, 18 November 2009

  2. RV 144 Primary Population Analyses Subgroup Analyses Basic Immunogenicity Next steps

  3. Final Analysis Meeting: 10 Sept 2009

  4. Primary Populations (Statistical Analysis Plan) • All primary analyses were pre-specified prior to trial unblinding • Study design considerations • Based on ITT analysis in HIV-uninfected subjects • Powered to reduce acquisition during the vaccination period by 25% • Powered to reduce post-vaccination acquisition by 50% • mITT analysis was used by the independent Data and Safety Monitoring Board to judge trial futility throughout the study and efficacy at the Interim Analysis

  5. Intent-to-Treat (ITT) Examines all subjects, regardless of HIV infection status, who were randomized to either vaccine or placebo arm (16,402 subjects analyzed) Includes 7 HIV infected subjects (5 vaccine, 2 placebo) discovered to be HIV infected at baseline by look-back analysis

  6. Efficacy (ITT) 52,985 person-years 132 infections (7 prevalent) Vaccine infections: 56 Placebo infections: 76 VE: 26.4% p=0.08 95% CI: -4.0, 47.9

  7. Per Protocol (PP) • 12,542 subjects analyzed • Excludes 3,853 subjects who were included in the mITT • 2,422 who did not receive all six study injections • 1,412 who received any injection “out of window” • 19 for other protocol violations • Excludes first 6 months (14%) of the 42-month trial period • Excludes 39 HIV-infected subjects (15 vaccine, 24 placebo), reducing the number of endpoints by 31%

  8. Efficacy (PP) 36,720 person-years 86 infections Vaccine infections: 36 Placebo infections: 50 VE: 26.2% p=0.16 95% CI: -13.3, 51.9

  9. Modified Intent-to-Treat (mITT) • Examines all HIV-uninfected subjects who were randomized • This was a pre-specified analysis in the Statistical Analysis Plan • Primary analysis for DSMB examinations throughout the trial • Any other outcome scenario (VE > 50%; VL effect only; no VE or VL effect) would have been based on the mITT as the primary analysis

  10. Efficacy (mITT) 52,985 person-years 125 infections Vaccine infections: 51 Placebo infections: 74 VE: 31.2% p=0.04 95% CI: 1.1, 52.1 (O’Brien-Fleming-adjusted)

  11. Endpoint Accrual Timeframes PP mITT ITT Randomization Screening Up to 45 days 0.5 1 2 3 (time in years) 6-month vaccination schedule 3 years of follow-up (every 6 mo.) ALVAC®-HIV (vCP1521) priming at week 0, 4, 12, 24 AIDSVAX® B/E gp120 boosting at week 12, 24

  12. Summary of Analyses Includes 5 vaccine and 2 placebo recipients who were HIV positive at baseline Decreased event numbers, lower precision

  13. RV 144 Primary Population Analyses Subgroup Analyses Basic Immunogenicity Next steps

  14. Baseline Risk-stratifiedTreatment Effects (mITT) VE for each risk category was statistically similar

  15. Exploratory Risk-stratified Analysis • The point estimate of VE in high-risk volunteers was very low with very large confidence intervals • Of the 125 infections • 12 infections were seen in same-gender sex risk • 2 infections were seen in CSW • Zero infections were seen in IDU • Of these 14 events, half occurred in each treatment group • The point estimates of VE in lower risk, heterosexual volunteers were higher with very large confidence intervals • These observations are exploratory and hypothesis-generating

  16. Efficacy (mITT):Evidence for Early, Waning Protective Effect? 52,985 person-years 125 infections Vaccine infections: 51 Placebo infections: 74 VE: 31.2% p=0.04 95% CI: 1.1, 52.1 (O’Brien-Fleming-adjusted)

  17. Cumulative Vaccine Efficacy Over Time (Kaplan-Meier-based estimates) When tested, efficacy did not decrease with time

  18. Conclusions • The mITT analysis demonstrates a modest, statistically significant protective effect, and this is supported by the trends observed in the ITT and PP populations • The mITT analysis is the most clinically relevant analysis as it: • Excludes volunteers with prior infection and reflects the study design and protocol • Does not assume that all four vaccinations are important • Does not assume that timing of all 4 vaccinations is critical • Limits bias compared to PP

  19. Questions Subgroup analyses are provocative but not statistically robust; inferences require caution • Was the modest protective effect limited to non-high risk individuals? • Was the modest protective effect early and non-durable? • As neither ALVAC-HIV nor AIDSVAX was previously tested for efficacy in this population, what is their respective contribution to the observed effect?

  20. RV 144 Primary Population Analyses Subgroup Analyses Basic Immunogenicity Next steps

  21. Disclaimer I am not Nicole Frahm…….

  22. RV144 Immunogenicity – Study Flow RV144 Immunogenicity – Study Flow Randomized list (EMMES) Laboratory blinded to vaccine status 200 participants 200 participants 200 participants IFN-γ/IL-2 ICS IFN-γ ELISpot LPA gp120/p24 BAb 0 and 12 0 and 6.5 0 and 12 Months gp160 (92TH023) - 162 peptide pool p24 (LAI) - 120 peptide pool Antigens A244 and MN gp120 IIIB p24 A244 and MN gp120 BH10 p24 AIDSVAX/ALVAC Match ALVAC (vCP1521)

  23. Study Arm for Immunogenicity Assays

  24. ELISpot responses – Vaccinees 6 months post-final vaccination ENV GAG SFC/106PBMC * P<0.05;**P<0.01 versus Placebo (N=38)

  25. IFN-/IL-2 ICS6 months post-final vaccination *P <0.0001 compared to placebo

  26. Ag-Specific Lymphoproliferation2 weeks post-final vaccination- FINAL DATA P<0.001 compared to placebo group - all Antigens

  27. Binding Antibody2 weeks post-final vaccination P<0.0001 compared to placebo group - all Antigens

  28. Phase I/II versus RV144

  29. Immunogenicity Summary • Direct ex vivo cellular immunogenicity assessed by cytokine production at 6 months following completion of immunization was CD4-mediated, but CD8 responses following in vitro stimulation not assessed • The vaccine regimen induced robust CMI as measured by LPA responses to HIV subtypes B and E Env and more moderately to p24 at 2 weeks post immunization • CI responses overall were predominantly to HIV Env

  30. Immunogenicity Summary (2) vCP1521 induced CD4 and antibody responses to the HIV-1 Gag antigen Induction of humoral immune responses was robust to both subtypes of HIV-1 gp120 and less so to p24 Both CMI and humoral immune responses were comparable to the earlier phase I/II trial Future work - Further definition of responding CD4 T cells, neutralizing antibody, ADCC and innate immunity

  31. RV 144 Primary Population Analyses Subgroup Analyses Basic Immunogenicity Next steps

  32. Organization of the Post-trial Effort ADVISORY GROUPS PA H Steering Committee Product Development Advisory Group Implications for future clinical development of this product MHRP - DAIDS Steering Committee Humoral & Innate Immunity RV144 Steering Committee Cellular Immunity Scientific Steering Committee Host Genetics Implications for future scientific inquiry into the result and evaluation/design of other candidates and studies Animal Models Scientific Advisory Groups

  33. Lessons Learned • “C4” • Lines of communication and dissemination of information must be clear, uniform, documentable (minutes, guidance, SOPs) • Risk management • Initiate damage control before the damage occurs • Hire sufficient personnel • Community engagement—never enough nor complete • Cultural sensitivity ↔ scientific integrity • 24 Sep to 20 Oct 2009

  34. Battle of El-Alamein26 Oct-5 Nov 1942

  35. Churchill address to Parliament, 10 Nov 1942 Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning. Henceforth Hitler's Nazis will meet equally well armed, and perhaps better armed troops. Hence forth they will have to face in many theatres of war that superiority in the air which they have so often used without mercy against other, of which they boasted all round the world, and which they intended to use as an instrument for convincing all other peoples that all resistance to them was hopeless....

  36. Acknowledgements • RV144 volunteers and community members • AFRIMS – US and Thai Component • Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH • Faculty of Tropical Medicine, Mahidol University • Global Solutions for Infectious Diseases • Henry M. Jackson Foundation for the Advancement of Military Medicine • Ministry of Public Health, Thailand • sanofi pasteur • U.S. Military HIV Research Program, Walter Reed Army Institute of Research; U.S. Army Medical Research and Materiel Command

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